IL-10 and TGF-ß1 gene polymorphisms in Greek patients with recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is one of the most frequent inflammatory disorders of the oral mucosa. Cytokines, which play an important role in RAS pathogenesis, participate directly or indirectly in normal, immunological and inflammatory processes and are secreted from cells belonging to innate and adaptive immunity as a consequence of microbial and antigenic stimuli. Gene polymorphisms in specific cytokines may predispose to RAS development. The aim of this study was the investigation and association of IL-10 and TGF-ß1 gene polymorphisms with RAS. MATERIAL AND METHODS: Study's cohort consisted of 60 Greek patients diagnosed with RAS, including 40 patients with minor, 10 patients with major and 10 with herpetiform aphthous ulcers. Forty age- and sex-matched control subjects were included in this study. DNA was extracted from whole blood samples of all patients and sequence-specific primers (SSP)-based polymerase chain reaction (PCR) was used for genotyping. Gene polymorphisms for cytokines IL-10 at loci -592 and -819 and for TGF-ß1 at codon 10 were detected. RESULTS: Significant differences between patients with minor RAS and healthy controls were recorded for IL-10 genotypes distribution at position -592 (p=0.042) and -819 (p=0.045) with predominance of C/A and C/T genotypes in RAS patients, respectively. Also, in patients with minor and herpetiform aphthous ulcerations, heterozygous TGF-ß1 genotype C/T at codon 10 was associated with increased risk of RAS (p=0.044 and p=0.020, respectively). CONCLUSIONS: These data provide evidence that genetic predisposition for RAS and possibly its specific clinical variants is related with the presence of gene polymorphisms for specific cytokines, including IL-10 and TGF-ß1, which, in turn, may vary according to geographic origin and genetic background.

Self-reported hair loss in patients with chronic spontaneous urticaria treated with omalizumab: an under-reported, transient side effect?

Omalizumab has been recently approved for treating patients with refractory to H1- antihistamines chronic spontaneous urticaria (CSU). Although hair loss is listed among omalizumab side effects, there are no available data to estimate its frequency. We describe for the first time hair loss as a side effect associated with omalizumab administration in three women, 38, 62 and 70 years old, suffering from refractory to H1-antihistamines CSU. This information was retrieved from their Chronic Urticaria Quality of Life Questionnaires. Despite this side effect, all patients agreed to continue omalizumab regular administration. Hair loss appeared to be transient, lasting up to four months. All cases finally benefited from omalizumab continuation.

Combined treatment with sitagliptin and vitamin D in a patient with latent autoimmune diabetes in adults.

UNLABELLED: Latent autoimmune diabetes in adults (LADA) is a relatively new type of diabetes with a clinical phenotype of type 2 diabetes (T2D) and an immunological milieu characterized by high titers of islet autoantibodies, resembling the immunological profile of type 1 diabetes (T1D). Herein, we report a case of a young male, diagnosed with LADA based on both clinical presentation and positive anti-glutamic acid decarboxylase antibodies (GAD-abs), which were normalized after combined treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4) (sitagliptin) and cholecalciferol. LEARNING POINTS: Anti-glutamic acid decarboxylase antibodies (GAD-abs) titers in young patients being previously diagnosed as type 2 diabetes (T2D) may help establish the diagnosis of latent autoimmune diabetes in adults (LADA).Sitagliptin administration in patients with LADA might prolong the insulin-free period.Vitamin D administration in patients with LADA might have a protective effect on the progression of the disease.

Sudden Bilateral Sensorineural Hearing Loss Associated with HLA A1-B8-DR3 Haplotype.

Sudden sensorineural hearing loss may be present as a symptom in systemic autoimmune diseases or may occur as a primary disorder without another organ involvement (autoimmune inner ear disease). The diagnosis of autoimmune inner ear disease is still predicated on clinical features, and to date specific diagnostic tests are not available. We report a case of bilateral sudden hearing loss, tinnitus, intense rotatory vertigo, and nausea in a female patient in which the clinical manifestations, in addition to raised levels of circulating immune complexes, antithyroglobulin antibodies, and the presence of the HLA A1-B8-DR3 haplotype, allowed us to hypothesize an autoimmune inner ear disease. Cyclosporine-A immunosuppressive treatment in addition to steroids helped in hearing recovery that occurred progressively with normalization of the hearing function after a five-month treatment. Cyclosporine-A could be proposed as a therapeutic option in case of autoimmune inner ear disease allowing the suspension of corticosteroids that, at high dose, expose patients to potentially serious adverse events.

Characteristics of patients with allergic rhinitis in an outpatient clinic: A retrospective study

Background: Allergic rhinitis affects a significant proportion of the European population. Few surveys have investigated this disorder in Greek adults. Our objective was to describe the characteristics of patients with allergic rhinitis in an adult outpatient clinic in Thessaloniki, Greece. Methods: We studied the medical records of adult patients referred to a Clinical Immunology outpatient clinic from 2001 to 2007. The diagnostic procedure was not changed during the whole study period, including the same questionnaire used at the time of diagnosis, skin prick tests, and serum specific IgE. Results: A total of 1851 patient files with diagnosed allergies were analysed and allergic rhinitis was confirmed in 711 subjects (38.4%). According to ARIA classification, persistent allergic rhinitis was more prevalent than intermittent (54.9% vs. 45.1%), while 60.8% of subjects suffered from moderate/severe disease. In multivariable analysis, factors associated with allergic rhinitis were age (for every 10 years increase, OR: 0.84, 95% CI: 0.77-0.91; p < 0.001); working in school environment (teachers or students) (OR: 1.46, 95% CI: 1.05---2.02; p = 0.023); parental history of respiratory allergy (OR: 2.41, 95% CI: 1.69-3.43; p < 0.001); smoking (OR: 0.71, 95%CI: 0.55-0.91; p = 0.007); presence of allergic conjunctivitis (OR: 6.16, 95% CI: 4.71---8.06;p < 0.001); and asthma (OR: 2.17, 95% CI: 1.57-3.01; p < 0.001). Analysis after multiple imputation corroborated the complete case analysis results. Conclusions: Allergic rhinitis was documented in 38.4% of studied patients and was frequently characterised by significant morbidity. Factors associated with allergic rhinitis provide insight into the epidemiology of this disorder in our region. Further studies on the general population would contribute to evaluating allergic rhinitis more comprehensively (AU)

Characteristics of patients with allergic rhinitis in an outpatient clinic: a retrospective study.

BACKGROUND: Allergic rhinitis affects a significant proportion of the European population. Few surveys have investigated this disorder in Greek adults. Our objective was to describe the characteristics of patients with allergic rhinitis in an adult outpatient clinic in Thessaloniki, Greece. METHODS: We studied the medical records of adult patients referred to a Clinical Immunology outpatient clinic from 2001 to 2007. The diagnostic procedure was not changed during the whole study period, including the same questionnaire used at the time of diagnosis, skin prick tests, and serum specific IgE. RESULTS: A total of 1851 patient files with diagnosed allergies were analysed and allergic rhinitis was confirmed in 711 subjects (38.4%). According to ARIA classification, persistent allergic rhinitis was more prevalent than intermittent (54.9% vs. 45.1%), while 60.8% of subjects suffered from moderate/severe disease. In multivariable analysis, factors associated with allergic rhinitis were age (for every 10 years increase, OR: 0.84, 95% CI: 0.77-0.91; p<0.001); working in school environment (teachers or students) (OR: 1.46, 95% CI: 1.05-2.02; p=0.023); parental history of respiratory allergy (OR: 2.41, 95% CI: 1.69-3.43; p<0.001); smoking (OR: 0.71, 95% CI: 0.55-0.91; p=0.007); presence of allergic conjunctivitis (OR: 6.16, 95% CI: 4.71-8.06; p<0.001); and asthma (OR: 2.17, 95% CI: 1.57-3.01; p<0.001). Analysis after multiple imputation corroborated the complete case analysis results. CONCLUSIONS: Allergic rhinitis was documented in 38.4% of studied patients and was frequently characterised by significant morbidity. Factors associated with allergic rhinitis provide insight into the epidemiology of this disorder in our region. Further studies on the general population would contribute to evaluating allergic rhinitis more comprehensively.

Association between the heme oxygenase-1 promoter polymorphism and renal transplantation outcome in Greece.

BACKGROUND: Heme oxygenase-1 (HO-1) is the enzyme that catabolizes heme into carbon monoxide, biliverdin, and free iron. The induction of this enzyme is an important cytoprotective mechanism, which occurs as an adaptive and beneficial response to a wide variety of oxidant stimuli. HO-1 has recently been suggested to protect transplants from ischemia/reperfusion and immunologic injury. HO-1 inducibility is mainly modulated by a (GT)(n) repeat polymorphism in the promoter region, and has been shown that short repeats (S) are associated with greater upregulation of HO-1, compared with long repeats (L). In the present study we investigated the influence of this HO-1 gene polymorphism on clinical outcome after transplantation and on renal transplant function. METHODS: DNA from 175 donor/recipient pairs who underwent transplantation between October 2002 and June 2007 was genotyped. We divided the HO-1 alleles into 2 subclasses, the S ≤ 27 repeats and L > 27 repeats. RESULTS: There has been significant relevance between the genotype of the donor and the outcome of the graft, as far as recipients with normal graft function and recipients with deteriorated graft function are concerned (P = .021). In patients with normal graft function, grafts from L-homozygotes were found in 24%, whereas in patients with deteriorated function, grafts from L-homozygotes exhibited in higher rate (50%). Neither the donor's nor the recipient's polymorphism influenced the graft survival (log-rank test P = .228 for the donors and log-rank test P = 0.844 for the recipients). There was no evidence of a gene-dose effect on graft survival (P = .469). Recipients of allografts from S-carriers donors had significantly lower serum creatinine levels at 24 months compared with recipients of allografts from L-homozygotes donors (P = .016).

HLA alleles and fissured tongue.

The aim of this study was to investigate the linkage between HLA and fissured tongue. Sixty- nine individuals with fissured tongue and 125 healthy volunteers were typed for HLA-DRB1*. The results showed increased frequency of HLA-DRB1*08 (P < 0.001), HLA-DRB1*14 (P < 0.01), HLA-DRB1*11 (P < 0.05) and HLA-DRB1*16 (P < 0.05), while HLA-DRB1*03 and HLA-DRB1*07 frequency was decreased (P < 0.05).

HLA-DQA1*0505 sharing and killer immunoglobulin-like receptors in sub fertile couples: report from the 15th International Histocompatibility Workshop.

This aim of the study was to investigate whether human leukocyte antigen (HLA)-DQA1*0505 sharing or the maternal killer immunoglobulin-like receptor (KIR) repertoire is associated with recurrent spontaneous abortion (RSA) or repeated implantation failure (RIF). The study included 224 couples with RSA, 61 couples with RIF, 182 fertile couples, and 10 couples with successful in vitro fertilization and embryo transfer (IVF)/ET at first cycle. HLA-DQA1*0505 typing using polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) was performed in 185 RSA (117 with alloimmune abnormalities and 68 of autoimmune etiology), 61 RIF and 182 control couples, and KIR genotyping using polymerase chain reaction-sequence-specific primer (PCR-SSP) in 167 RSA and 55 RIF cases as well as 46 RSA and 10 IVF controls. No differences in DQA1*0505 sharing were found between patients and controls. In RSA and RIF women, the ratio of inhibitory to activating KIRs was slightly lower (1.53 and 1.85 vs 2.03 in controls). The analysis of maternal inhKIR and fetal HLA-C molecule pairs showed that the 'less inhibiting' combination KIR2DL3-C1 was found in higher percentage in subfertile (mainly RIF) than in fertile couples. In contrast, the percentage of cases possessing the 'strong inhibiting' combination KIR2DL1-C2 was lower in the RSA and RIF groups in comparison with that in the control groups (17.36% vs 23.91 and 16.36% vs 40%, respectively). In women with >or= 6 implantation failures, the KIR2DL1-C2 combination was not found in any of them (P = 0.0014), and the KIR2DL3-C1 combination was not found in the control IVF group. The results oppose the suggestion that increased HLA-DQA1*0505 sharing predispose to RSA or RIF. The KIR2DL3-C1 combination (or lack of the KIR2DL1-C2 one) is associated with implantation failure.

Major histocompatibility complex class II (DRB1*, DQA1*, and DQB1*) and DRB1*04 subtypes' associations of Hashimoto's thyroiditis in a Greek population.

Hashimoto's thyroiditis (HT) is an autoimmune disease resulting from complex interactions between genetic and environmental factors. The disease is associated with certain human leukocyte antigen (HLA) class II alleles in various populations. We aimed to determine in this study, for the first time in a Greek population, the association of HLA-DRB1*, -DQA1*, and -DQB1* alleles with HT. HLA-DRB1*, -DQA1*, and -DQB1* alleles' and -DRB1*04 subtypes' distribution was evaluated in 125 patients with HT and in 500 healthy control individuals by using a DNA-based sequence-specific primer method. Chi(_)squared tests and Bonferroni correction method were applied in the statistical analysis of the data. Significantly higher frequency of DRB1*04 (24.8% vs 7.7%, P < 0.0001) was observed in HT patients, while HLA-DRB1*07 was significantly decreased (2.8% vs 7.9%, P < 0.05). HLA-DRB1*04 subtyping showed a significant increase of DRB1*0405 (21% vs 7.8%, P < 0.0001) in HT patients. Also significant high frequencies of DQB1*0201 (14.8% vs 8.2%, P < 0.001), DQB1*0302 (18.8% vs 7.0%, P < 0.0001), and DQA1*0301 (25.6% vs 7.8%, P < 0.0001) were recorded in the patient group. Conducting the first research of this kind in a Greek population, our study tries to provide an evaluation of the prevalence of HT relating to HLA-DRB1*0405, and we report a relative risk of 2.7 for HT in a Greek population.

14th International HLA and Immunogenetics Workshop: report from the reproductive immunology component.

The aim of the study was to investigate whether human leukocyte antigen (HLA) allele sharing between partners or the maternal killer immunoglobulin-like receptor (KIR) repertoire is associated with recurrent spontaneous abortion (RSA) and repeated implantation failure after in vitro fertilization (IVF)/embryo transfer. From a total population of 158 RSA couples, 40 couples with repeated implantation failures (IVF) and 81 control couples, reported by five different laboratories, analysis was performed for (a) HLA sharing in 50 RSA, 31 IVF and 31 control couples, (b) DQA1*0505 sharing/homozygosity among partners in 108 RSA, 40 IVF and 36 control couples, and (c) the women's KIR repertoire in 46 RSA, 26 IVF and 36 control wives. RSA couples were divided into alloimmune aborter (RSAallo) and autoimmune aborter (RSAauto). The results oppose to the suggestion that increased HLA sharing per se or a limited maternal KIR repertoire predisposes to RSA or IVF failure. However, the observation of a slightly higher percentage of DQA1*0505 sharing in the RSAauto and the IVF group needs further investigation. The ratio of inhibitory to activating KIR (actKIR) was slightly lower in RSAallo and IVF women (1.9 vs 2.6 in controls), while in a high percentage of these women, the standard receptors of the KIR A haplotype were combined with actKIR/s of the haplotype B (66.6% and 45.4% vs 20% and 15.3% in RSAauto and control groups). This may suggest a possible involvement of actKIRs in embryo implantation and the maintenance of pregnancy and also requires further investigation.

HLA antigens in Greek children with allergic bronchial asthma.

The aim of our study was to investigate the genetic linkage between mite allergic bronchial asthma and HLA class I and II antigens and haplotypes. Sixty Greek children with allergic bronchial asthma due to mite sensitivity (Dermatophagoides pteronyssinus and Dermatophagoides farinae) and their family members were typed for HLA class I and II antigens (total 263 subjects). One hundred and twenty-five healthy, unrelated Greek children without medical history of atopy were also typed as control group. Major histocompatibility complex class I and II gene analysis revealed that only HLA-DRB1*04 and HLA-DQA1*0301 alleles are possibly important factors in the development of atopic asthma in Greek children with sensitivity to mites. No significant differences among the HLA-DRB1*04 subtypes have been established. Transmission disequilibrium test revealed that no specific HLA-A, -B, -DRB1, -DQA1 and -DQB1 alleles were transmitted preferentially to the affected children. HLA-DQB1*0301-4 alleles were associated with high levels of total serum immunoglobulin E in affected children. The study of the HLA haplotypes failed to demonstrate any significant association between any extended or natural selection haplotype and mite allergic bronchial asthma in Greek children.

Interleukin-1 beta and tumor necrosis factor-alpha in normal/infertile men.

Cytokines play an important role in intercellular communications. Human sperm contains a wide spectrum of cytokines. such as interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). Their effects on semen quality are subject to debate. The aim of this study was to determine concentrations of IL-1beta and TNF-alpha in normal fertile men and in different groups of male infertility in an attempt to clarify the physiology and suggest possible clinical uses. Sixty-six subfertile male patients with varicocele (n = 22). infection of accessory genital glands (n = 14), varicocele plus infection (n = 4), chronic epididymitis (n = 8). post-renal transplantation status (n = 5), idiopathic oligoasthenoteratospermia (n = 9), cryptorchidism (n = 1), and homozygous beta-thalassemia (n = 3) as well as 5 male controls were studied through history, physical examination, spermiograms, plasma basal hormonal levels, and IL-1beta and TNF-alpha levels in seminal fluid. There was no significant statistical difference regarding IL-1beta and TNF-alpha among fertile men and subfertile patients of any cause. 1L-1beta and TNF-alpha were in tight positive correlation (p<.001). Determination of IL-1beta and TNF-alpha does not provide useful information in male routine infertility workup. Nevertheless, a better understanding of these mediators in semen of normal men and infertile patients may contribute to a new approach to the management of male infertility.

Wegener's granulomatosis presenting with bilateral facial nerve palsy.

Primary manifestation of Wegener's granulomatosis in the mucosa of the middle ear is rather rare, and has been reported as presenting with serous otitis media, chronic otitis media, sensorineural hearing loss, and, in rare instances, unilateral facial palsy. Bilateral facial palsy has never been reported. This last fact constitutes the interest in our report of a 23-year-old female patient who presented with symptoms of recurrent bilateral otitis media, eventually developing sensorineural hearing loss and bilateral facial palsy. Soon thereafter neurological symptoms appeared and lung extension was noted. Histological examination of repeated biopsies taken from the nasal and middle ear mucosa was not conclusive for the suspected disease, and c-ANCA titers were also initially repeatedly negative. Eventually, positive lung biopsy and elevated c-ANCA titers when the patient had developed pulmonary granulomas confirmed the diagnosis of Wegener's granulomatosis. Mastoid surgery with facial nerve decompression of the most severely afflicted side did not result in the recovery of facial nerve function. Medical therapy with corticosteroids and cyclophosphamide improved the clinical picture but were ineffective in improving the bilateral sensorineural hearing loss and the facial paralysis on the operated side. We would contribute to the literature a unique case of bilateral facial nerve palsy due to Wegener's granulomatosis.

Can HLA typing predict the outcome of grass pollen immunotherapy?

OBJECTIVE: The aim of this study was to investigate the relationship between HLA molecules and the positive or negative response of atopic patients to specific immunotherapy (SIT). METHODS: We studied 42 atopic multisensitive patients undergoing grass pollen immunotherapy, 42 parents of patients (30 mothers and 12 fathers) and 173 control individuals. HLA class I and class II antigens were typed by a microlymphocytotoxicity test. The typing of DRB1* alleles for atopic patients and their parents was based on the reverse hybridization principle, while for the control group, DNA-RFLP and PCR-SSP methods were used. RESULTS: The frequency of B14 and DRB1*1101-4 antigens/alleles, as well as the A2B5DR11 haplotype, showed a statistically significant difference in those patients who responded to immunotherapy. On the other hand, HLA-A28, B8 and DRB1*0301 antigens/alleles, as well as the frequency of the A1B8 and A1B8DR3 haplotypes, were found to be significantly higher in patients who responded poorly to SIT. DISCUSSION: Our findings support the hypothesis that treatment responsiveness may show an association to HLA molecules, which could thus play a role in the immunological selection and monitoring of atopic patient candidacy for SIT.

Cytokines in the human ovary: presence in follicular fluid and correlation with leukotriene B4.

PURPOSE: This study was undertaken to correlate the follicular levels of interleukin (IL)-1 alpha, IL-2, tumor necrosis factor-alpha (TNF-alpha), and leukotriene (LT) B4 with oocyte maturity, fertilization, and achievement of pregnancy. METHODS: The material was obtained from 22 women undergoing IVF, 8 of whom became pregnant and 14 of whom did not. RESULTS: All of the studied cytokines and LT B4 were found in follicular fluids, but there were no significant differences according to oocyte maturity, fertilization, embryo quality, and achievement of pregnancy. On the other hand, a significant positive correlation was found between IL-1 alpha and TNF-alpha, IL-1 alpha, and LT B4 as well as between TNF-alpha and LT B4 in follicular fluids with subsequently fertilized oocytes. CONCLUSIONS: It seems that IL-1 alpha, TNF-alpha and LT B4 may take part in the process of follicle wall degradation, and their follicular correlations may suggest more optimal follicular and oocyte development and maturation.

Haplotypes of human leukocyte antigens among patients with nasopharyngeal cancer in Greece.

The concept that the major histocompatibility complex (MHC) plays an important role in the pathogenesis of nasopharyngeal cancer (NPC) in several ethnic groups has gained increased attention during the last 15 years. Earlier studies have suggested that an increased risk of NPC is associated with specific phenotypes of human leukocyte antigens (HLA). The present study was performed to examine the association of HLA specificities and haplotypes with NPC in a Greek population. In a genotypical study of 53 patients, a significant association between the haplotype HLA-B5DR11 and NPC was found, mainly in patients > 45 years. Also, the above haplotype was significantly associated with longer disease-free interval. HLA-B5 and HLA-B5DR11 were more often seen among patients with squamous cell histology than among those with the undifferentiated type. These results suggest that MHC loci are probably implicated in the pathogenesis and outcome of NPC in Greek patients.

Differentiation between renal allograft rejection and cyclosporine toxicity: a clinicopathological study.

The differentiation between cyclosporine nephrotoxicity (CyN) and acute rejection (AR) still remains a matter of intensive research. In a retrospective study over the last 2 years, we assessed the clinical and histopathological data of 43 episodes of renal dysfunction in 39 renal transplant recipients immunosuppressed with cyclosporine (CyA). Ten episodes (23.2%) were identified as AR and 10 (23.2%) as acute CyN; in six cases (13.9%), signs of both AR and CyN were found. Fever (80%), oliguria (50%), and edema (50%) were prominent features in AR, but not in CyN. Renal blood flow was higher in the nephrotoxicity group and for corresponding degree of renal dysfunction. Significant hyperuricemia (greater than 8 mg/dL) was a prominent finding in CyN (80%) and to a lesser extent in AR (20%). The helper to suppressor cell ratio in the peripheral blood remained stable or slightly decreased in all cases with CyN, but increased in 70% of the cases with AR. CyN was associated with significantly higher whole blood CyA levels (P less than 0.005) and there was a positive correlation between plasma creatinine and CyA levels during the nephrotoxicity episodes (P less than 0.02). Diffuse mononuclear cell infiltrate was observed in 90% of the biopsies with AR and only in 20% with CyN (P less than 0.005). Concerning the extent of the tubular lesions, no significant differences were observed between the two groups. In contrast, vascular lesions such as arterial endothelial proliferation (P less than 0.05), hyalinosis (P less than 0.05), and glomerular capillary thrombi (P less than 0.05) were more commonly seen in nephrotoxicity biopsies.(ABSTRACT TRUNCATED AT 250 WORDS)